Coinfections in human papillomavirus associated cancers and prophylactic recommendations.

The Human Papillomavirus (HPV) infection is responsible for more than 80% of reported cervical cancer and other virus-associated tumours. Although this global threat can be controlled using effective vaccination strategies, a growing perturbation of HPV infection is an emerging coinfection likely to increase the severity of the infection in humans. Moreover, these coinfections prolong the HPV infections, thereby risking the chances for oncogenic progression. The present review consolidated the clinically significant microbial coinfections/co-presence associated with HPV and their underlying molecular mechanisms. We discussed the gaps and concerns associated with demography, present vaccination strategies, and other prophylactic limitations. We concluded our review by highlighting the potential clinical as well as emerging computational intervention measures to kerb down HPV-associated severities.

Elucidating the molecular role of MUC5B in progressive lung adenocarcinoma: Prospects for early diagnosis.

Gel-forming mucin MUC5B is significantly deregulated in lung adenocarcinoma (LUAD), however, its role in tumor progression is not yet clearly understood. Here, we used an integrated computational-pipeline-initiated with gene expression analysis followed by network, functional-enrichment, O-linked glycosylation analyses, mutational profiling, and immune cell infiltration estimation to functionally characterize MUC5B gene in LUAD. Thereafter, clinical biomarker validation was supported by the overall survival (OA) and comparative expression profiling across clinical stages using computational algorithms. The gene expression profile of LUAD identified MUC5B to be significantly up-regulated (logFC: 2.36; p-value: 0.01). Network analysis on LUAD interactome screened MUC5B-related genes, having key enrichment in immune suppression and O-linked glycosylation with serine-threonine-rich tandem repeats being highly glycosylated. Furthermore, positive correlation of mutant MUC5B with immune cells in tumor microenvironment (TME) such as cancer-associated fibroblasts and myeloid-derived suppressor cells indicates TME-mediated tumor progression. The positive correlation with immune inhibitors suggested the enhanced tumor proliferation mediated by MUC5B. Structural stability due to genetic alterations identified overall rigid N-H-backbone dynamics (S2 : 0.756), indicating an overall stable mutant protein. Moreover, the low median OA (<50 months) with a hazard ratio of 1.4 and clinical profile of MUC5B gene showed high median expression corresponding to lymph node (N2) and tumor (T3) stages. Our study concludes by highlighting the functional role of O-glycosylated and mutant MUC5B in promoting LUAD by immune suppression. Further, clinical gene expression validation of MUC5B suggests its potential role as a diagnostic biomarker for LUAD metastasis.

Unravelling the molecular mechanistic pathway underlying the anticancer effects of kaempferol in colorectal cancer: a reverse pharmacology network approach.

Colorectal cancer (CRC) is the third most diagnosed and highly fatal malignancy, presenting serious health concerns worldwide. The search for an effective cure for CRC is challenging and poses a serious concern. Kaempferol is a potent anti-cancerous bioactive compound often suggested for treating various cancers, including CRC. However, its underlying molecular mechanism against CRC remains unclear. The present study delves into kaempferol's molecular pathways and underlying molecular mechanisms against CRC targets. The target protein-coding genes for kaempferol were retrieved, and the CRC-associated genes were curated. Twelve common targets with a disease specificity index of > 0.6 were validated for their protein expression at different stages of CRC. Over-expressed USP1, SETD7, POLH, TDP1 and RACGAP1 were selected for further studies. The binding affinities of kaempferol to the corresponding proteins were evaluated using molecular docking and Molecular Dynamics (MD) simulations. SETD7 exhibited the highest binding affinity with the lowest binding energy (- 8.06 kcal/mol). Additionally, the MD simulation, and MM-PBSA conferred SETD7-kaempferol complex had the least root-mean-square deviation with lower interaction energy and higher conformational stability. The protein-protein interaction of SETD7 constructed revealed direct interactors, namely, DNMT1, FOXO1, FOXO3, FOXO4, H3-3B, H3-4, H3C12, H3C13, SETD7, SIRT1 and TP53, have a potential role in cancer progression through FOXO signalling. In summary, our study revealed kaempferol's multi-target and synergistic effect on multiple CRC targets and its underlying mechanisms. Finally, the study recommends in-vitro and in-vivo trials for validation of anti-cancerous drugs for CRC.

FN1 and cancer-associated fibroblasts markers influence immune microenvironment in clear cell renal cell carcinoma.

BACKGROUND: Altered tumor microenvironment (TME) is characterized in clear cell renal cell carcinoma (ccRCC) as a result of the heterogeneity observed in the TME. Modulations in TME have shown tumor metastasis promotion; hence, identifying TME-based biomarkers can be critical for theranostics application. METHODS: Here, we performed an integrated systems biology approach utilizing differential gene expression, network metrics and clinical samples cohorts to prioritize the major deregulated genes and their associated pathways specific for metastasis. RESULTS: The gene expression profiling of 140 ccRCC samples resulted in 3657 differentially expressed genes, from which a network of 1867 up-regulated genes were further computed using network metrics for screening hub-genes. The specific pathways of ccRCC entailed through functional enrichment analysis of the hub-gene clusters indicated the role of the identified hub-genes in the enriched pathways, further validating the functional significance of the hub-genes. The positive correlation of TME cells, namely cancer-associated fibroblasts (CAFs) and its biomarkers (FAP and S100A4) with FN1, signified the role of hub-gene signaling for promoting metastasis in ccRCC. Thereafter, comparative expression, differential methylation, genetic alteration and overall survival analysis were analyzed to validate the screened hub-genes. CONCLUSIONS: The hub-genes were validated and prioritized by correlating with expression-based parameters, including histological grades, tumor, metastatic and pathological stages (based on median transcript per million; analysis of variance [ANOVA], P ≤ 0.05) from a clinically curated ccRCC dataset to further substantiate the translational benefits of the screened hub-genes as potential diagnostic biomarkers for ccRCC.

Comprehensive analysis on the diagnostic role of circulatory exosome-based miR-92a-3p for osteoblastic metastases in prostate adenocarcinoma.

Prostate adenocarcinoma (PRAD) is the second leading cause of death in men and the key factor that attributes to the severity and higher mortality rates is the tumor's ability to promote osteoblastic metastases (OM). Currently, no blood-based biomarkers are present that bridges the crosstalk between PRAD and OM progression. Conversely, circulatory microRNAs (miRNAs) are gaining interest among the scientific community for its potential as blood-based markers for cancer detection. Using computational pipeline, this study screened exosome-based miRNA that is functionally regulating OM in PRAD. We retrieved the expression profile of miRNA, mRNA from PRAD microarray, and RNA-Seq samples deposited in global repositories and identified the differentially expressed miRNAs (DEMs) and differentially expressed genes. Thereafter, the average expression of the miRNAs was identified in extracellular vesicle specifically in exosomes. Survival analysis and clinical profiling identified functionally significant miR-92a-3p to be a key factor in OM. This was further examined by the interactions with various noncoding RNA elements, transcription factors, oncogenes, tumor suppressor genes, and protein kinases regulated by miR-92a-3p. Identifying the expression pattern, nodal metastasis, Gleason score, and hazard ratio deciphered the critical role of the targets regulated by miR-92a-3p. Further, binding association analyzed through energy, seed match and accessibility showed the miRNA-targets involved in cytokine, TGF-ß, and Wnt signaling having close regulatory role in promoting OM. Our findings highlight the potent role of miR-92a-3p as blood-based diagnostic biomarker for OM. The comprehensive insights from our study can be elemental in designing diagnostic biomarker for PRAD.

NFX1-123: A potential therapeutic target in cervical cancer.

NFX1-123 is a splice variant isoform of the NFX1 gene. It is highly expressed in cervical cancers caused by HPV, and NFX1-123 is a protein partner with the HPV oncoprotein E6. Together, NFX1-123 and E6 affect cellular growth, longevity, and differentiation. The expression status of NFX1-123 in cancers beyond cervical and head and neck cancers, and its potential as therapeutic target, have not been investigated. TSVdb of TCGA was used to quantify NFX1-123 expression in 24 cancers compared with normal tissues. The NFX1-123 protein structure was predicted and then submitted to retrieve suitable drug molecules. The top four compounds, found to bind in silico to NFX1-123, were tested experimentally to determine their effects on NFX1-123-related cellular growth, survival, and migration. 46% of cancers (11 of 24 had significant differences in NFX1-123 expression, with nine having had greater NFX1-123 expression, when compared with adjacent normal tissues. Bioinformatics and proteomic predictive analysis modeled the three-dimensional structure of NFX1-123, and drug libraries were screened for high-binding affinity compounds using this modeled structure. Seventeen drugs with binding energies ranging from -1.3 to -10 Kcal/mol were identified. The top four compounds were used to treat HPV- and HPV+ cervical cancer cell lines, three of which (Ropitoin, R428 and Ketoconazole) reduced NFX1-123 protein levels, inhibited cellular growth, survival, and migration, and enhanced the cytotoxicity of Cisplatin. These findings highlight cancers expressing high levels of NFX1-123, and drugs that target it, may reduce cellular growth, survival, and migration, making NFX1-123 a potential novel therapeutic target.

Systems biology approach to understand the interplay between Bacillus anthracis and human host genes that leads to CVDs.

Humans infected with invasive Bacillus anthracis (B. anthracis) have a very poor prognosis and are at high risk for developing cardiovascular diseases (CVDs) and shock. Several bacterial elements probably have significant pathogenic roles in this pathogenic process of anthrax. In our current work, we have analysed the molecular level interactions between B. anthracis and human genes to understand the interplay during anthrax that leads to the CVDs. Our results have shown dense interactions between the functional partners in both host and the B. anthracis Gene interaction network (GIN). The functional enrichment analysis indicated that the clusters in the host GIN had genes related to hypoxia and autophagy in response to the lethal toxin; and genes related to adherens junction and actin cytoskeleton in response to edema toxin play a significant role in multiple stages of the disease. The B. anthracis genes BA_0530, guaA, polA, rpoB, ribD, secDF, metS, dinG and human genes ACTB, EGFR, EP300, CTNNB1, ESR1 have shown more than 50 direct interactions with the functional partners and hence they can be considered as hub genes in the network and they are observed to have important roles in CVDs. The outcome of our study will help to understand the molecular pathogenesis of CVDs in anthrax. The hub genes reported in the study can be considered potential drug targets and they can be exploited for new drug discovery.

Bioactive phytocompounds against specific target proteins of Borrelia recurrentis responsible for louse-borne relapsing fever: Genomics and structural bioinformatics evidence.

Louse-borne relapsing fever (LBRF) with high untreated mortality caused by spirochete Borrelia recurrentis is predominantly endemic to Sub-Saharan Africa and has re-emerged in parts of Eastern Europe, Asia and Latin America due to population migrations. Despite subtractive evolution of lice-borne pathogenic Borrelia spp. from tick-borne species, there has been no comprehensive report on conservation of protein targets across tick and lice-borne pathogenic Borrelia nor exploration of phytocompounds that are toxic to tick against lice. From the 19 available whole genomes including B. recurrentis, B. burgdorferi, B. hermsii, B. parkeri and B. miyamotoi, conservation of seven drug targets (>80% domain identity) viz. 30 S ribosomal subunit proteins (RSP) S3, S7, S8, S14, S19, penicillin-binding protein-2 and 50 S RSP L16 were deciphered through multiple sequence alignments. Twelve phytocompounds (hydroxy-tyrosol, baicalein, cis-2-decanoic acid, morin, oenin, rosemarinic acid, kaempferol, piceatannol, rottlerin, luteolin, fisetin and monolaurin) previously explored against Lyme disease spirochete B. burgdorferi when targeted against LBRF-causing B. recurrentis protein targets revealed high multi-target affinity (2%-20% higher than conventional antibiotics) through molecular docking. However, based on high binding affinity against all target proteins, stable coarse-grained dynamics (fluctuations <1 Å) and safe pharmacological profile, luteolin was prioritized. The study encourages experimental evaluation of the potent phytocompounds and similar protocols for investigating other emerging vector-borne diseases.

Consolidated knowledge-guided computational pipeline for therapeutic intervention against bacterial biofilms - a review.

Biofilm-associated bacterial infections attributed to multifactorial antimicrobial resistance have caused worldwide challenges in formulating successful treatment strategies. In search of accelerated yet cost-effective therapeutics, several researchers have opted for bioinformatics-based protocols to systemize targeted therapies against biofilm-producing strains. The present review investigated the up-to-date computational databases and servers dedicated to anti-biofilm research to design/screen novel biofilm inhibitors (antimicrobial peptides/phytocompounds/synthetic compounds) and predict their biofilm-inhibition efficacy. Scrutinizing the contemporary in silico methods, a consolidated approach has been highlighted, referred to as a knowledge-guided computational pipeline for biofilm-targeted therapy. The proposed pipeline has amalgamated prominently employed methodologies in genomics, transcriptomics, interactomics and proteomics to identify potential target proteins and their complementary anti-biofilm compounds for effective functional inhibition of biofilm-linked pathways. This review can pave the way for new portals to formulate successful therapeutic interventions against biofilm-producing pathogens.

Potential Signature Therapeutic Biomarkers TOP2A, MAD2L1, and CDK1 in Colorectal Cancer: A Systems Biomedicine-Based Approach.

Colorectal cancer is the third deadliest and fourth most diagnosed cancer. It is heterogeneously driven by varied mutations and mutagens, and thus, it is challenging for targeted therapy. The rapid advancement of high-throughput technology presents considerable opportunities for discovering new colon cancer biomarkers. In the present study, we have explored and identified the biomarkers based on molecular interactions. We curated cancer datasets that were not micro-dissected and performed gene expression analysis. The protein-protein interactions were curated, and a network was constructed for the up-regulated genes. The hub genes were analyzed using 12 different topological parameters. The correlation analysis selected TOP2A, CDK1, CCNB1, AURKA, and MAD2L1 as hub genes. Further, survival analysis was performed to determine the effectiveness of the hub gene on the patient's survival rate. Our findings explore various transcription factors such as E2F4, FOXM1, E2F6, MAX, and SIN3A, along with kinases CSNK2A1, MAPK14, CDK1, CDK4, and CDK2, as potential molecular signatures and aid researchers in understanding the pathophysiological mechanisms underlying CRC development and thus providing novel therapeutic and diagnostic recourse. Furthermore, investigating miRNAs, we focused on hsa-miR-215-5p, hsa-miR-192-5p, and hsa-miR-193b-3p due to their observed impact on a diverse set of colorectal cancer genes. Thereby, the current approach brings into light CRC- related genes at the RNA and protein levels that can potentially act as novel biomarkers opening doors to diagnostic and treatment purposes.

Translational protein RpsE as an alternative target for novel nucleoside analogues to treat MDR Enterobacter cloacae ATCC 13047: network analysis and molecular dynamics study.

The pathogenic Enterobacter cloacae subsp. cloacae str. ATCC 13047 has contemporarily emerged as a multi-drug resistant strain. To formulate an effective treatment option, alternative therapeutic methods need to be explored. The present study focused on Gene Interaction Network study of 46 antimicrobial resistance genes to reveal the densely interconnecting and functional hub genes in E. cloacae ATCC 13047. The AMR genes were subjected to clustering, topological and functional enrichment analysis, revealing rpsE (RpsE), acrA (AcrA) and arnT (ArnT) as novel therapeutic drug targets for hindering drug resistance in the pathogenic strain. Network topology further indicated translational protein RpsE to be exploited as a promising drug-target candidate for which the structure was predicted, optimized and validated through molecular dynamics simulations (MDS). Absorption, distribution, metabolism and excretion screening recognized ZINC5441082 (N-Isopentyladenosine) (Lead_1) and ZINC1319816 (cyclopentyl-aminopurinyl-hydroxymethyl-oxolanediol) (Lead_2) as orally bioavailable compounds against RpsE. Molecular docking and MDS confirmed the binding efficacy and protein-ligand complex stability. Furthermore, binding free energy (Gbind) calculations, principal component and free energy landscape analyses affirmed the predicted nucleoside analogues against RpsE protein to be comprehensively examined as a potential treatment strategy against E. cloacae ATCC 13047.

In silico structure evaluation of BAG3 and elucidating its association with bacterial infections through protein-protein and host-pathogen interaction analysis.

BAG3, a co-chaperone protein with a Bcl-2-associated athanogene (BAG) domain, has diverse functionalities in protein-folding, apoptosis, inflammation, and cell cycle regulatory cross-talks. It has been well characterised in cardiac diseases, cancers, and viral pathogenesis. The multiple roles of BAG3 are attributed to its functional regions like BAG, Tryptophan-rich (WW), isoleucine-proline-valine-rich (IPV), and proline-rich (PXXP) domains. However, to study its structural impact on various functions, the experimental 3D structure of BAG3 protein was not available. Hence, the structure was predicted through in silico modelling and validated through computational tools and molecular dynamics simulation studies. To the best of our knowledge, the role of BAG3 in bacterial infections is not explicitly reported. We attempted to study them through an in-silico protein-protein interaction network and host-pathogen interaction analysis. From structure-function relationships, it was identified that the WW and PXXP domains were associated with cellular cytoskeleton rearrangement and adhesion-mediated response, which might be involved in BAG3-related intracellular bacterial proliferation. From functional enrichment analysis, Gene Ontology terms and topological matrices, 18 host proteins and 29 pathogen proteins were identified in the BAG3 interactome pertaining to Legionellosis, Tuberculosis, Salmonellosis, Shigellosis, and Pertussis through differential phosphorylation events associated with serine metabolism. Furthermore, it was evident that direct (MAPK8, MAPK14) and associated (MAPK1, HSPD1, NFKBIA, TLR2, RHOA) interactors of BAG3 could be considered as therapeutic markers to curb down intracellular bacterial propagation in humans.

FN1 encoding fibronectin as a pivotal signaling gene for therapeutic intervention against pancreatic cancer.

The delayed diagnosis of pancreatic cancer has resulted in rising mortality rate and low survival rate that can be circumvented using potent theranostics biomarkers. The treatment gets complicated with delayed detection resulting in lowered 5-year relative survival rate. In our present study, we employed systems biology approach to identify central genes that play crucial roles in tumor progression. Pancreatic cancer genes collected from various databases were used to construct a statistically significant interactome with 812 genes that was further analysed thoroughly using topological parameters and functional enrichment analysis. The significant genes in the network were then identified based on the maximum degree parameter. The overall survival analysis indicated through hazard ratio [HR] and gene expression [log Fold Change] across pancreatic adenocarcinoma revealed the critical role of FN1 [HR 1.4; log2(FC) 5.748], FGA [HR 0.78; log2(FC) 1.639] FGG [HR 0.9; log2(FC) 1.597], C3 [HR 1.1; log2(FC) 2.637], and QSOX1 [HR 1.4; log2(FC) 2.371]. The functional significance of the identified hub genes signified the enrichment of integrin cell surface interactions and proteoglycan syndecan-mediated cell signaling. The differential expression, low overall survival and functional significance of FN1 gene implied its possible role in controlling metastasis in pancreatic cancer. Furthermore, alternate splice variants of FN1 gene showed 10 protein coding transcripts with conserved cell attachment site and functional domains indicating the variants' potential role in pancreatic cancer. The strong association of the identified hub-genes can be better directed to design potential theranostics biomarkers for metastasized pancreatic tumor.

Organ-specific host differential gene expression analysis in systemic candidiasis: A systems biology approach.

Patients admitted to the hospital with coronavirus disease (COVID-19) are at risk for acquiring mycotic infections in particular Candidemia. Candida albicans (C. albicans) constitutes an important component of the human mycobiome and the most common cause of invasive fungal infections. Invasive yeast infections are gaining interest among the scientific community as a consequence of complications associated with severe COVID-19 infections. Early identification and surveillance for Candida infections is critical for decreasing the COVID-19 mortality. Our current study attempted to understand the molecular-level interactions between the human genes in different organs during systematic candidiasis. Our research findings have shed light on the molecular events that occur during Candidiasis in organs such as the kidney, liver, and spleen. The differentially expressed genes (up and down-regulated) in each organ will aid in designing organ-specific therapeutic protocols for systemic candidiasis. We observed organ-specific immune responses such as the development of the acute phase response in the liver; TGF-pathway and genes involved in lymphocyte activation, and leukocyte proliferation in the kidney. We have also observed that in the kidney, filament production, up-regulation of iron acquisition mechanisms, and metabolic adaptability are aided by the late initiation of innate defense mechanisms, which is likely related to the low number of resident immune cells and the sluggish recruitment of new effector cells. Our findings point to major pathways that play essential roles in specific organs during systemic candidiasis. The hub genes discovered in the study can be used to develop novel drugs for clinical management of Candidiasis.

Non-steroidal anti-inflammatory drugs ketorolac and etodolac can augment the treatment against pneumococcal meningitis by targeting penicillin-binding proteins.

BACKGROUND: Streptococcus pneumoniae is the principal etiological agent of acute bacterial meningitis (ABM) which has fatal outcome in children and elderly. Due to poor blood-brain barrier (BBB) permeation, conventional ß-lactam antibiotics fail to establish the requisite bactericidal concentration in central nervous system leading to resistance in meningeal infections. The present study intended to identify potential therapeutic alternatives against Streptococcal meningitis. METHODS: Virtual screening, pharmacokinetics/pharmacodynamics (PK/PD) and anti-bacterial evaluations were employed to screen potential drugs. Molecular docking and structural dynamics simulations were performed to analyze the binding affinity and interaction stability of the drugs against the conventional Penicillin binding protein (PBP) targets. Screened drugs were also checked for interactions with other possible Streptococcal targets and relevant host targets. RESULTS: Non-steroidal anti-inflammatory drugs (NSAIDs) ketorolac and etodolac exhibiting high BBB-permeation and anti-bacterial potency were identified. Ketorolac and etodolac possessed uniform binding affinities against PBP1A, PBP2X, PBP2B and PBP3 with low inhibition constants (<50 µM). Against PBP2B and PBP3, higher binding affinities were observed for ketorolac (-6.45 and -6Kcal/mol respectively) and etodolac (-6.36 and -6.55Kcal/mol respectively) than penicillin (-5.95 and -5.85Kcal/mol respectively) and cefotaxime (-5.08 and -5.07Kcal/mol respectively). The binding affinities were contributed by conventional H-bonds and non-canonical interactions with active site residues of PBPs. Structural dynamics simulations further indicated the overall stability of the drug-bound complexes through minimal overall average root-mean square fluctuations (RMSFs) (<1.0 Å). The average binding affinities of Ketorolac and Etodolac with PBPs were marginally higher than other Streptococcal targets and comparable to their conventional inflammatory targets. CONCLUSION: Pharmacological and structural profiles indicated that ketorolac and etodolac can potentially subdue the cause and effects of streptococcal meningitis and hence encourage experimental validations.

A comprehensive review on genomics, systems biology and structural biology approaches for combating antimicrobial resistance in ESKAPE pathogens: computational tools and recent advancements.

In recent decades, antimicrobial resistance has been augmented as a global concern to public health owing to the global spread of multidrug-resistant strains from different ESKAPE pathogens. This alarming trend and the lack of new antibiotics with novel modes of action in the pipeline necessitate the development of non-antibiotic ways to treat illnesses caused by these isolates. In molecular biology, computational approaches have become crucial tools, particularly in one of the most challenging areas of multidrug resistance. The rapid advancements in bioinformatics have led to a plethora of computational approaches involving genomics, systems biology, and structural biology currently gaining momentum among molecular biologists since they can be useful and provide valuable information on the complex mechanisms of AMR research in ESKAPE pathogens. These computational approaches would be helpful in elucidating the AMR mechanisms, identifying important hub genes/proteins, and their promising targets together with their interactions with important drug targets, which is a crucial step in drug discovery. Therefore, the present review aims to provide holistic information on currently employed bioinformatic tools and their application in the discovery of multifunctional novel therapeutic drugs to combat the current problem of AMR in ESKAPE pathogens. The review also summarizes the recent advancement in the AMR research in ESKAPE pathogens utilizing the in silico approaches.

Gene interaction network approach to elucidate the multidrug resistance mechanisms in the pathogenic bacterial strain Proteus mirabilis.

Proteus mirabilis is one among the most frequently identified pathogen in patients with the urinary tract infection. The multidrug resistance exhibited by P. mirabilis renders the treatment ineffective, and new progressive strategies are needed to overcome the antibiotic resistance (AR). We have analyzed the evolutionary relationship of 29 P. mirabilis strains available in the National Center for Biotechnology Information-Genome database. The antimicrobial resistance genes of P. mirabilis along with the enriched pathways and the Gene Ontology terms are analyzed using gene networks to understand the molecular basis of AR. The genes rpoB, tufB, rpsl, fusA, and rpoA could be exploited as potential drug targets as they are involved in regulating the vital functions within the bacterium. The drug targets reported in the present study will aid researchers in developing new strategies to combat multidrug-resistant P. mirabilis.

Genome sequencing and molecular characterisation of XDR Acinetobacter baumannii reveal complexities in resistance: Novel combination of sulbactam-durlobactam holds promise for therapeutic intervention.

Emerging nosocomial strains of Acinetobacter baumannii are of recent concern as they are expressing extensive drug resistance (XDR). Using whole-genome sequencing and molecular characterisation analysis, the current study reveals the presence of carbapenemase genes in 92.86% of studied Indian isolates. These included blaOXA-51 , blaOXA-23 , blaOXA-58 , and blaNDM genes, with over a third expressing dual carbapenemase genes. As per the MLST scheme, IC2Oxf /CC2Pas was the predominant clone, with 57.14% isolates belonging to this lineage. The presence of these carbapenemase genes resulted in sulbactam (SUL) resistance (MIC: 16-256 µg/ml) in all of the studied isolates. The efficacy of durlobactam (DUR), a novel ß-lactamase inhibitor that also inhibits PBP2 was assessed through in silico intermolecular interaction analysis. Several nonsynonymous single nucleotide polymorphisms were identified in PBP2 (G264S, I108V, S259T) and PBP3 (A515V, T526S) sequences. Minimal variations were recorded in the protein backbone dynamics in active-site motifs of wild-type and mutants, which correlated with negligible binding energy fluctuations for the PBP3-SUL (-5.85 ± 0.04 kcal/mol) and PBP2-DUR (-5.16 ± 0.66 kcal/mol) complexes. Furthermore, higher binding affinities and low inhibition constants were noted in OXA23-DUR (-7.36 kcal/mol; 4.01 µM), OXA58-DUR (-6.44 kcal/mol; 19.07 µM), and NDM-DUR (-6.82 kcal/mol; 10.01 µM) complexes when compared with the conventional drugs avibactam and aztreonam. Stable interaction profiles of DUR with carbapenemases can possibly restore SUL activity against both PBP3WT and PBP3MTs . The study establishes the efficacy of the novel SUL-DUR combination as a successful treatment strategy in combating emerging XDR strains of A. baumannii.

Novel cyclohexanone compound as a potential ligand against SARS-CoV-2 main-protease.

No commercially available drug candidate has yet been devised which is unique to and not repurposed against SARS-CoV-2 and has high efficacy or safe toxicity profile or both. Taking curcumin as a reference compound, we identified a new commercially available cyclohexanone compound, ZINC07333416 with binding energy (-8.72 kcal/mol) better than that of popularly devised anti-Covid-19 drugs like viral protease inhibitor Lopinavir, nucleoside analogue Remdesivir and the repurposed drug hydroxychloroquine when targeted to the active-site of SARS-CoV-2 Main protease (Mpro) through docking studies. The ligand ZINC07333416 exhibits crucial interactions with major active site residues of SARS-CoV-2 Mpro viz. Cys145 and His41 involving in the protease activity; as well as GLU-166 and ASN-142 which plays the pivotal role in the protein-dimerization. The protein-ligand stable interaction was further confirmed with molecular dynamics simulation (MDS) studies. Based on virtual assessment, ZINC07333416 also have significant values in terms of medicinal chemistry, pharmacokinetics, synthetic accessibility and anti-viral activity that encourage its experimental applications against COVID-19.

Gene interaction network studies to decipher the multi-drug resistance mechanism in Salmonella enterica serovar Typhi CT18 reveal potential drug targets.

Salmonella enterica subsp. enterica serovar Typhi, a human enteric pathogen causing typhoid fever, developed resistance to multiple antibiotics over the years. The current study was dedicated to understand the multi-drug resistance (MDR) mechanism of S. enterica serovar Typhi CT18 and to identify potential drug targets that could be exploited for new drug discovery. We have employed gene interaction network analysis for 44 genes which had 275 interactions. Clustering analysis resulted in three highly interconnecting clusters (C1-C3). Functional enrichment analysis revealed the presence of drug target alteration and three different multi-drug efflux pumps in the bacteria that were associated with antibiotic resistance. We found seven genes (arnA,B,C,D,E,F,T) conferring resistance to Cationic Anti-Microbial Polypeptide (CAMP) molecules by membrane Lipopolysaccharide (LPS) modification, while macB was observed to be an essential controlling hub of the network and played a crucial role in MacAB-TolC efflux pump. Further, we identified five genes (mdtH, mdtM, mdtG, emrD and mdfA) which were involved in Major Facilitator Superfamily (MFS) efflux system and acrAB contributed towards AcrAB-TolC efflux pump. All three efflux pumps were seen to be highly dependent on tolC gene. The five genes, namely tolC, macB, acrA, acrB and mdfA which were involved in multiple resistance pathways, can act as potential drug targets for successful treatment strategies. Therefore, this study has provided profound insights into the MDR mechanism in S. Typhi CT18. Our results will be useful for experimental biologists to explore new leads for S. enterica.